CN113336705B - Cannabidiol-2-imidazole-1-formate and application thereof - Google Patents
Cannabidiol-2-imidazole-1-formate and application thereof Download PDFInfo
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- CN113336705B CN113336705B CN202110906029.6A CN202110906029A CN113336705B CN 113336705 B CN113336705 B CN 113336705B CN 202110906029 A CN202110906029 A CN 202110906029A CN 113336705 B CN113336705 B CN 113336705B
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- cannabidiol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Abstract
The invention discloses a large-diameter tubeThe invention relates to cannabidiol-2-imidazole-1-formate and application thereof, in particular to a compound shown in a formula I, a stereoisomer or pharmaceutically acceptable salt or ester thereof, the cannabidiol-2-imidazole-1-formate has a protection effect on nerve cell injury, can be used for preparing neuroprotective drugs and has practical application value in medical production,
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a novel cannabidiol derivative and a preparation method and application thereof.
Background
Cannabidiol (CBD) is one of the major phenolic chemical components in industrial cannabis, and has received much attention for its broad pharmacological effects and efficacy. The current research shows that the cannabidiol has wide therapeutic properties and has obvious improvement effect on neurological diseases including anxiety, schizophrenia, addiction, neurodegenerative diseases and neonatal hypoxic-ischemic encephalopathy. In 2018, the Cannabis diol oral liquid of Giewar pharmaceutical company is approved by the United states food and drug administration for treating epilepsy caused by Dravet syndrome and Lennox-Gastaut syndrome in patients of two years old or more. Therefore, the cannabidiol is a natural product with great application prospect in the fields of medicine and food.
Due to the diversity and novelty of chemical structure and biological activity, natural products are an inexhaustible source for the discovery of active lead compounds. Cannabidiol is a natural product with great application prospect, based on the structure of cannabidiol, cannabidiol derivatives are designed and synthesized, and the activity of the cannabidiol derivatives is researched, so that the cannabidiol derivatives are an important way for obtaining higher-activity compounds, and have important significance for preparing novel nerve cell protection medicines.
The existing cannabidiol and derivatives thereof have numerous action targets but weak action on each target, and have certain toxicity, so that the application of the cannabidiol and the derivatives thereof is limited. The development of derivatives with specific groups to improve their selectivity for specific targets or to increase their effect on multiple targets is a major research direction in the future.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel cannabidiol derivative and a preparation method thereof. The invention also provides the compound, pharmaceutically acceptable salts or solvates thereof, a pharmaceutical composition containing the compound and application of the compound and the pharmaceutical composition in preparing nerve cell protection medicaments.
The compounds of the invention have the structure shown in formula I:
the preparation method of the cannabidiol derivative provided by the invention comprises the following steps: carrying out reaction on cannabidiol with a structure shown in a formula II and carbonyldiimidazole with a structure shown in a formula III in the presence of a solvent to obtain a compound with a structure shown in a formula I.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects:
(1) the invention provides a novel cannabidiol derivative, which is cannabidiol-2-imidazole-1-formate, has a protective effect on nerve cell injury, can be prepared into a neuroprotective medicament, and has practical application value in medicine production.
(2) According to the preparation method provided by the invention, the raw materials are cannabidiol with a structure shown in a formula II and carbonyl diimidazole with a structure shown in a formula III, no catalyst is used, and the solvent is a common solvent, so that the raw materials are cheap and easy to obtain.
(3) The preparation method provided by the invention has the advantages of mild conditions and low energy consumption.
(4) The preparation method provided by the invention has the advantages that the yield of the main product reaches 52.2%, and the yield is higher.
In some embodiments of the invention, the method of preparation comprises the following general route:
in some embodiments of the invention, the solvent is tetrahydrofuran.
In some embodiments of the invention, the molar ratio of cannabidiol to carbonyldiimidazole is 1: 3.
In some embodiments of the present invention, the preparation method specifically comprises heating and refluxing the reaction mixture for 2 hours, concentrating by rotary evaporation, dissolving with dichloromethane, washing with water, drying with anhydrous magnesium sulfate, rotary evaporation, and separating and purifying by column chromatography.
The invention also provides a pharmaceutical composition, which comprises the cannabidiol-2-imidazole-1-formate or the pharmaceutically acceptable salt thereof or the solvate of the compound, and one or more excipients, diluents, fillers and the like;
preferably, the pharmaceutical composition is formulated in the form of powder or granules.
The invention also provides application of cannabidiol-2-imidazole-1-formate or a pharmaceutically acceptable salt thereof or a solvate of the compound or a pharmaceutical composition containing the compound in preparation of a nerve cell protection medicament.
Detailed Description
The conception and the resulting technical effects of the present invention will be further described with reference to specific embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention. The method is a conventional method unless otherwise specified. The materials are commercially available from the open literature unless otherwise specified.
Example 1 preparation of cannabidiol-2-imidazole-1-carboxylate
The synthetic route is shown as the following formula:
3.14g (10 mmol) of cannabidiol, 4.86g (30 mmol) of carbonyl diimidazole and 20 mL of tetrahydrofuran are added into a 50 mL three-neck flask, heated and refluxed for 2 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography to obtain 2.13 g of colorless liquid, and the yield is 52.2%.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1H NMR (300 MHz, CDCl3) δ: 8.40 (s, 1H), 7.58 (s, 1H), 6.62 (d, J = 27.0 Hz, 1H), 5.54 (s, 1H),5.35(s, 1H), 4.62 (s, 1H), 4.43 (s, 1H), 3.5 (s, 1H), 2.54 – 2.00 (m, 6H), 1.79 – 1.49 (m, 7H), 1.26 (s, 8H), 0.88 (s, 3H)。
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H]+: theoretical value is 409.24857, found 409.24866.
The results of the nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum prove that the preparation method provided by the invention can be used for effectively preparing the cannabidiol-2-imidazole-1-formate.
Example 2 determination of the neuronal injury protection Effect of cannabidiol-2-imidazole-1-carboxylate
Cannabidiol and the compound obtained in example 1 were dissolved in DMSO under sterile conditions to prepare a 20 mM stock solution. BV2 cells were inoculated in a 96-well plate, a cell injury model was constructed by stimulation with glutamic acid and corticosterone, respectively, and after 12 hours of culture, cannabidiol and the compound obtained in example 1 were added to the culture medium, diluted to 5, 2.5, 1, 0.5, 0.25, 0.1 μ M, 5 multiple wells per group were set, and culture was continued for 72 hours, 20 μ L of MTT reagent was added to each well, and culture was continued for 0.5 hour. MTT working solution was discarded, 150. mu.l DMSO was added to each well, and the mixture was shaken gently in a shaker at room temperature for 10 min and mixed well. The experiment was carried out on a normal control group, a glutamic acid-induced BV2 cell injury group and a corticosterone-induced BV2 cell injury group. The 96-well plate was placed in an microplate reader at a wavelength of 450 nm to measure the OD value, and the cell survival rate was calculated.
Cell survival (%) = (each treatment group OD-blank OD)/(control group OD-blank OD) × 100%.
The test results are shown in Table 1.
The results in table 1 show that the compounds of the present invention have antagonistic effect on BV2 cytotoxicity caused by glutamic acid and BV2 cytotoxicity caused by corticosterone, and can improve cell survival rate, and the activity of the compounds of the present invention is higher than that of cannabidiol at the same concentration, which indicates that the compounds of the present invention have good protection effect on nerve cell damage, and have potential application prospect in medicine production.
Although the present invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it is not limited to the above-described embodiments, but may be modified or improved on the basis of the present invention, as will be apparent to those skilled in the art. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (5)
1. A cannabidiol derivative compound is characterized in that the derivative is cannabidiol-2-imidazole-1-formate and pharmaceutically acceptable salts thereof, wherein the chemical structural formula of the cannabidiol-2-imidazole-1-formate is shown as a formula I:
formula I.
2. The application of the compound of the cannabidiol derivative in the preparation of the nerve cell protection medicine is characterized in that the derivative is cannabidiol-2-imidazole-1-formate or pharmaceutically acceptable salt thereof, wherein the chemical structural formula of the cannabidiol-2-imidazole-1-formate is shown as a formula I:
formula I.
3. Use of a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more excipients, diluents, fillers for the manufacture of a neuroprotective medicament.
4. The use according to claim 2, wherein the neural cell is glial cell BV 2.
5. The use according to claim 3, wherein the neural cell is glial cell BV 2.
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| CN113735709B (en) * | 2021-09-17 | 2022-03-18 | 中国农业科学院农产品加工研究所 | Cannabidiol-2-butyrate and application thereof |
| CN114349695B (en) * | 2022-03-07 | 2022-05-20 | 中国农业科学院农产品加工研究所 | Cannabidiol-2-nicotinate and application thereof |
| CN114292224B (en) * | 2022-03-07 | 2022-05-20 | 中国农业科学院农产品加工研究所 | Cannabidiol-2- (N-acetyl) piperidine acid ester and application thereof |
| CN114315680B (en) * | 2022-03-07 | 2022-07-19 | 中国农业科学院农产品加工研究所 | Cannabidiol-2-pyrrolidine acid ester and application thereof |
| CN114292241B (en) * | 2022-03-07 | 2022-07-19 | 中国农业科学院农产品加工研究所 | Cannabidiol-2-dioxopiperazinoate and application thereof |
| CN116983263B (en) * | 2023-09-28 | 2023-12-19 | 中国农业科学院农产品加工研究所 | Embedding system of dihydrocannabidiol diimidazole formate and preparation method and application thereof |
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Effective date of registration: 20220106 Address after: 150431 First Committee of Ben street, Binxi Town, Bin County, Harbin City, Heilongjiang Province Patentee after: Heilongjiang Fengyou hemp planting Co.,Ltd. Address before: 100193 No. 2 Old Summer Palace West Road, Beijing, Haidian District Patentee before: INSTITUTE OF FOOD SCIENCE AND TECHNOLOGY, CHINESE ACADEMY OF AGRICULTURAL SCIENCES |